Infertility is a difficult and stressful condition for patients and treating physicians alike. Couples struggling with infertility often find that the problem is not a female issue. The failure to conceive within 1 year occurs in about 15% of couples, and male infertility is considered the causative reason in about 40% of problems related to conception. Male infertility therefore continues to be a clinical challenge of increasing significance.
Male infertility commonly refers to the inability of a male to induce pregnancy in a fertile female after a period of 12 months, without the use of contraceptives. Male infertility affects one in 20 men, with over 90% of cases caused by abnormal semen quality. Abnormal semen quality can be categorized as an abnormal sperm production with shape or motility defects, or abnormal low sperm number. Low sperm number has been defined as a decrease in the concentration of spermatozoa to below 15 million/ml, or a total number of below 39 million. Although sexual function is normal in men suffering from abnormal semen quality, there is a reduced count of normal, functional spermatozoa and/or a disproportionate number of spermatozoa that are dysfunctional in either motility or morphology.
The complex process of sperm transport through the female reproductive tract begins at the time of ejaculation. Millions of spermatozoa are deposited in the anterior vagina during coitus. A vast number of these spermatozoa are lost though the vaginal introitis, but a pool of spermatozoa, suspended in seminal fluid and vaginal plasma transudate, remain in the posterior vaginal fornix. For human males with normal sperm production, within minutes of ejaculation 1.5 ml to 5.0 ml of semen containing between 200 and 500 million sperm is deposited. Freshly ejaculated sperm are unable or poorly able to fertilize. Rather, they must first undergo a series of physiologic changes known collectively as capacitation before being capable of penetrating the egg. Capacitation occurs in vivo while the sperm reside in the female reproductive tract, and results in the spermatozoa gaining the ability to undergo fusion with the female oocyte during the acrosome reaction and subsequently proceed to fertilization. Human sperm generally require a period of several hours for capacitation to occur. Typically capacitation of spermatozoa is assisted by the sperm being suspended in a pool of seminal fluid and vaginal plasma transudate, which remains following intercourse in the posterior vaginal fornix and intermixes with endocervical mucus at the opening of the cervical os. The positioning and composition of this pool allows the sperm to capacitate and swim up into the cervical canal and the uterus, ultimately finding the oocyte for fertilization.
Male infertility resulting from an abnormal sperm quality disrupts the natural mechanism for fertilization. Sperm capacitation and fertilization are invariably unsuccessful because the number of healthy spermatozoa released into the vaginal fornix is lacking. To overcome this problem, various assisted reproduction techniques have been introduced over the last several decades, including therapeutic interventions such as artificial insemination, in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT) or intracytoplasmic sperm injection (ICSI) has allowed scientists and clinicians to treat poor fertility in some individuals or to store sperm, oocytes or embryos for use at other locations or times. With these in vitro techniques, different methods may be used to isolate the healthy, motile (swimming) sperm from dead sperm, such as centrifugation, swim-up, separation columns, and the like. For example, one such method known as “sperm swim-up” isolates healthy sperm by a swim-up method. See, e.g., FIGS. 4A-4E. Briefly, sperm swim-up tubes are prepared by placing wash media in a round bottom tube. Sperm are layered under this wash media using a needle and syringe. The tubes are incubated undisturbed, and the wash medium (that the motile sperm have swum up into) is removed and centrifuged. A pellet of motile sperm is recovered, which is then layered once again under fresh wash medium for analysis or use. Other methods, such as column separation, may alternatively be used.
While the assisted reproduction technologies described above have revolutionized the treatment of infertile couples, there is still room for improvement. Although sperm can be extended in media for use in sperm analysis and diagnostic tests, existing assisted reproduction techniques generally decrease the normal survival and function of sperm. These in vitro techniques involve the sperm spending time outside of the human body, in a test tube or in culture, and can be damaging to healthy, functional spermatozoa, resulting in losses of motile sperm and damage to sperm DNA. Although sperm typically survive for days in the females of most species, sperm survival in vitro is typically only half as long, and sperm from males with poor quality ejaculates may survive for even shorter time periods in vitro. Indeed, sperm survival is suboptimal outside of the female reproductive tract.
Further, despite its proven success, still only 30% of infertile couples undergoing IVF therapy are successful in having a child. Due to the 70% failure rate of IVF procedures and the high medical bills associated with them, the majority of infertile couples choose not to go forward with IVF procedures. Other couples have moral or religion-based objections to IVF.
In light of this, it would be beneficial to provide a more successful and affordable treatment for couples who are seeking to conceive but are hindered by a diagnosis of male infertility. While most current treatment modalities focus on improving the sperm count or quality of the male, the present invention looks at the female partner as an important variable for improving the chances of conception with an infertile male partner. Indeed, since procreation involves both a male and a female, perhaps optimizing the environment in the female may improve the chances of survival of the infertile male's spermatozoa, no matter how decreased in number or viability they may be.
Prior art vaginal lubricants are generally limited to vaginally inserted artificial lubricants. Commercially available replacement vaginal lubricants, such as KY Jelly, Replens, Astroglide, and Femglide have all been shown to decrease sperm motility or even have spermicidal effects. Because of numerous medical articles reporting the adverse actions of vaginal lubricants on sperm, it is currently contraindicated for infertility patients to use any of the above types of vaginal lubricants to treat insufficiency. Such lubricants do not intravaginally capacitate sperm or intravaginally provide a medium for gradient sperm differentiation.
U.S. Pat. No. 6,322,493 and U.S. Pat. No. 6,702,733, both to Thompson and incorporated herein by reference in their entirety, teach of the topical use of menthol in combination with L-arginine as a means for treating decreased female sexual arousal. The topical menthol has two functions, initial mucous membrane vasodilatation, and secondarily as a permeability enhancer to facilitate the transport of L-arginine into the clitoral tissues to affect and generate a clitoral erection.
U.S. published patent application 2005/0244520 to Thompson, and incorporated herein by reference in its entirety, describes the reflex production of normal physiological vaginal lubrication as a treatment for decreased female sexual arousal, or female sexual dysfunction. This document defines a combination of menthol, or a related cooling compound, and L-arginine topically applied to the clitoris to evoke reflex vaginal lubrication, to treat lubrication insufficiency relative to female sexual dysfunction.
U.S. Published Patent Application 2007/0060653 to Thompson and incorporated herein by reference in its entirety, teaches the use of the topical menthol in combination with L-arginine to treat lubrication insufficiency ascribed to 75% of infertile women. This document describes how the induction of a physiological vaginal transudate by the topical clitoral application of menthol and L-arginine can support the function and viability of spermatozoa, initially in the hostile vaginal environment, and ultimately in the cervical mucus. It teaches that maximizing production of this physiological vaginal transudate will optimize spermatozoa survival and function in the female reproductive tract, thereby increasing the odds of conception in females suffering from female sexual dysfunction.
While recent advances in treating female infertility may be useful for their intended purposes, there remains an unmet need for couples suffering from infertility in which the male is diagnosed as being infertile. It would therefore be beneficial to provide a method for increasing the chances of survival in the vagina of healthy sperm produced by a male suffering from abnormal semen quality. It would also be advantageous to provide a method to minimize or prevent the damage imparted to sperm caused by methods such as in vitro sperm swim-up and capacitation techniques, centrifugal separation, freezing, or the like. It would further be beneficial to provide an in vivo method of treatment in which the male's sperm do not undergo extracorporeal handling or treatment.